This invention relates to improved drug compositions useful in the treatment of male erectile dysfunction and also to methods of treatment. More particularly, this invention discloses specific formulations containing the pharmacological agents phentolamine mesylate, papaverine hydrochloride, and alprostadil (prostaglandin E1) in a novel buffer and the administration of such formulations to mammals (including humans) to treat male impotence.
Impotence is a common medical disorder affecting about 20 million men in the U.S. alone. Male erectile dysfunction has been defined as the inability to achieve or maintain an erection sufficient for intercourse (Impotence, National Institutes of Health Consensus Development Panel on Impotence Conference, JAMA 1993, 270, 83-90). The dominant etiology for this condition is arterial insufficiency associated with cardiovascular disease. Male erectile dysfunction adversely impacts the quality of life, being frequently associated with depression, anxiety, and low self-esteem. Although male erectile dysfunction represents a major clinical problem, treatment for this condition remains problematic and unsatisfactory.
One of the least invasive therapies available entails the use of a vacuum constriction-device on the penis to produce an erection. The physiology of the penis is such that blood flows in through arteries deep within the tissue while blood flows out through veins near the skin surface. By placing a plastic cylinder over the shaft of the penis and employing a vacuum pump to restrict venous blood flow from the penis, the corpus cavernosum penile tissue becomes engorged with trapped blood and an erection is produced. Common patient complaints are that this device is interruptive to the sex act, has a short duration of effectiveness, and can cause tissue damage to the penis, such as necrosis, with extended use.
Penile prosthesis implantation is an alternative treatment of erectile dysfunction. This therapy entails surgically implanting a mechanical device inside the penis (for example see U.S. Pat. No. 5,065,744 to Zumanowshky). This device can be a semi-rigid malleable rod or a fluid inflated tube which can be operated by the patient to achieve an erection. Although this method does not affect the ability to urinate, ejaculate, or have an orgasm, the surgery required to implant the prosthesis can lead to pain, infection, and scarring.
Recent insights into the physiological mechanism of penile erection have led to the development of other therapies for the treatment of erectile dysfunction. Preliminary studies have shown that during sexual arousal, nitric oxide molecules are released into the surrounding tissue from nerve endings and endothelial cells in the genitals. These nitric oxide molecules then cause the enzyme guanylate cyclase to produce cyclic guanosine monophosphate (cGMP) which lowers the level of intracellular calcium in the surrounding medium and allows for the relaxation of smooth muscle cells. In the penis, the relaxation of the corpus cavernosal smooth muscle cells permits increased blood flow into the cavernosal spaces which leads to greater intracavernosal pressure thereby producing penile rigidity.
It follows then that a pharmacological agent which inhibits the breakdown of cGMP would have the potential to prolong or enhance penile erections during sexual stimulation. The drug sildenafil (Viagra™, Pfizer, Inc.) is one such pharmacological agent which, when given orally, has shown some success in this manner (Terret, N. K. et al. Bioorg. Med. Chem. Lett. 1996, 6, 1819-1824).
Other types of oral therapies which are available to treat erectile dysfunction by different means include centrally-acting drugs such as atipamezole (Farmos Orion) which is an α-adrenergic blocker, apomorphine (Pentech Pharmaceuticals) which is a dopaminergic agonist, and phentolamine (Vasomax™, Zonagen) which is another α-adrenergic blocker/vasodilator. This family of drugs appears to act by expanding arteries and relaxing penile tissue which, in combination, entraps blood in the penis thereby producing an erection. However, some oral therapies may have drawbacks with respect to efficacy and side effects. Therefore, in those cases it would be beneficial to treat impotence directly by administering medicaments directly on/into the penis itself. These modes of administration may also minimize the dosage of the medicament needed.
One alternative route for administering vasoactive agents like those mentioned above is by transdermal administration to the penis. The compound alprostadil (prostaglandin E1) is formulated as a cream (Macrochem) which is absorbed into the penile tissue. Alprostadil has been shown to bind to specific receptors in penile tissue which is accompanied by an increase in cellular cyclic adenosine monophosphate (cAMP) levels. The physiological mechanism, as described with cGMP above, results in a decrease of intracellular calcium in the cytoplasm and the relaxation of smooth muscle cells. These vasodilatory effects result in rapid arterial inflow and expansion of the sinusoidal spaces within the penis. This action then restricts venous outflow from the penis whereby penile rigidity develops. Another vasoactive agent, papaverine hydrochloride, is formulated into a patch (PharmaPatch, Pharmedia) to be applied to the skin of the penis and acts as a non-specific phosphodiesterase inhibitor to maintain cGMP levels in a similar sort of mechanism as described above which produces an erection. These external treatments of the skin surface of the penis suffer from the drawback that the sex partner comes into contact with the drug during intercourse and can be adversely affected.
The above-mentioned pharmacological agents and routes of administration represent therapies for the treatment of erectile dysfunction which can be successful for about 75-80% of the 20 million men having erectile dysfunction. However, for the remaining impotent population, a different treatment is needed which often includes intraurethral and/or intracavernosal injection therapy.
Currently, there are two FDA-approved injection therapies available (Caverject®, Pharmacia-Upjohn; and Edex™, Schwartz Pharma), both of which employ alprostadil as the active component. Caverject® is commercially marketed as a freeze-dried powder containing the active ingredient alprostadil in a base of lactose, sodium citrate, and benzyl alcohol. When reconstituted with water, Caverject® is injected into the intracavernosal space of the penis. Similarly, EDEX™ is a lyophilized powder containing alprostadil, α-cyclodextrin, and anhydrous lactose. It is also reconstituted with water before injection into the intracavernosal space of the penis. A urethral suppository of alprostadil (MUSE™, Vivus, Inc.) has also recently been introduced into the market; however, it has shown disappointing clinical results (Biotech. Newswatch, Jun. 15, 1998, 4-5). Not all impotent men respond to alprostadil therapy alone.
In order to treat these individuals who were non-responsive to alprostadil, Zorgniofti et al. (J. Urol. 133:39-41 (1985), incorporated herein by reference) demonstrated that the intracavernosal injection of a combination of papaverine hydrochloride and phentolamine mesylate rapidly produced transitory penile tumescence which could be followed by an erection in response to sexual stimulation.
Similarly, Althof et al. (J. Sex Marital Ther. 17(2):101-112 (1991), incorporated herein by reference) reported that intracavernosal injection of papaverine hydrochloride and phentolamine mesylate resulted in improved erectile ability in about 84% of patients injected. However, there was a high dropout rate (57%) in this study because 25% of patients developed fibrotic nodules, 30% had abnormal liver functions, and 19% experienced bruising of the penile tissue. In another study using the same combination of phentolamine mesylate and papaverine hydrochloride, the intracavernous injection of this combination led to marked penile fibrosis in the patients injected (see Larsen, E. K. et al. J. Urol. 137, 292-293 (1987) incorporated herein by reference).
Therefore, a need exists for a safe and effective alternative treatment for impotence which minimizes the drawbacks of the therapies described above to those currently available.